ERTAPENEM SODIUM

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ertapenem for injection and other antibacterial drugs, Ertapenem for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Treatment Ertapenem for injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with the following moderate to severe infections caused by susceptible isolates of the designated microorganisms [see Dosage and Administration ( 2 )]. Ertapenem for injection is a penem antibacterial indicated in adult patients and pediatric patients (3 months of age and older) for the treatment of the following moderate to severe infections caused by susceptible bacteria: Complicated intra-abdominal infections. ( 1.1 ) Complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis. ( 1.2 ) Community-acquired pneumonia. ( 1.3 ) Complicated urinary tract infections including pyelonephritis. ( 1.4 ) Acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections. ( 1.5 ) Ertapenem for injection is indicated in adults for the prophylaxis of surgical site infection following elective colorectal surgery. ( 1.6 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ertapenem for injection and other antibacterial drugs, Ertapenem for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.7) 1.1 Complicated Intra-Abdominal Infections Ertapenem for injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated intra-abdominal infections due to Escherichia coli, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, or Bacteroides uniformis . 1.2 Complicated Skin and Skin Structure Infections, Including Diabetic Foot Infections without Osteomyelitis Ertapenem for injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated skin and skin structure infections, including diabetic foot infections without osteomyelitis due to Staphylococcus aureus (methicillin susceptible isolates only), Streptococcus agalactiae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacteroides fragilis, Peptostreptococcus species, Porphyromonas asaccharolytica, or Prevotella bivia . Ertapenem for injection has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies ( 14 )]. 1.3 Community Acquired Pneumonia Ertapenem for injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with community acquired pneumonia due to Streptococcus pneumoniae (penicillin susceptible isolates only) including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates only), or Moraxella catarrhalis. 1.4 Complicated Urinary Tract Infections Including Pyelonephritis Ertapenem for injection is indicated for the treatment of adult patients and pediatric patients (3 months of age and older) with complicated urinary tract infections including pyelonephritis due to Escherichia coli, including cases with concurrent bacteremia, or Klebsiella pneumoniae. 1.5 Acute Pelvic Infections Including Postpartum Endomyometritis, Septic Abortion and Post Surgical Gynecologic Infections Er …

2 DOSAGE AND ADMINISTRATION Do not mix or co-infuse Ertapenem for Injection with other medications. Do not use diluents containing dextrose (α–D–glucose) . ( 2.1 ) Ertapenem for Injection should be infused over 30 minutes in both the Treatment and Prophylactic regimens. ( 2.1 ) Dosing considerations should be made in adults with advanced or end-stage renal impairment and those on hemodialysis. ( 2.4 , 2.5 ) Treatment regimen: • Adults and pediatric patients 13 years of age and older. The dosage should be 1 gram once a day intravenously or intramuscularly. ( 2.2 ) • Patients 3 months to 12 years of age should be administered 15 mg/kg twice daily (not to exceed 1 g/day intravenously or intramuscularly.) ( 2.2 ) • Intravenous infusion may be administered in adults and pediatrics for up to 14 days or intramuscular injection for up to 7 days. ( 2.1 ) Prophylaxis regimen for adults: • 1 gram single dose given 1 hour prior to elective colorectal surgery. ( 2.3 ) 2.1 Instructions for Use in All Patients For Intravenous or Intramuscular Use DO NOT MIX OR CO-INFUSE ERTAPENEM FOR INJECTION WITH OTHER MEDICATIONS. DO NOT USE DILUENTS CONTAINING DEXTROSE (α-D-GLUCOSE). Ertapenem for Injection may be administered by intravenous infusion for up to 14 days or intramuscular injection for up to 7 days. When administered intravenously, Ertapenem for Injection should be infused over a period of 30 minutes. Intramuscular administration of Ertapenem for Injection may be used as an alternative to intravenous administration in the treatment of those infections for which intramuscular therapy is appropriate. 2.2 Treatment Regimen 13 years of age and older The dose of Ertapenem for Injection in patients 13 years of age and older is 1 gram (g) given once a day [see Clinical Pharmacology (12.3) ]. 3 months to 12 years of age The dose of Ertapenem for Injection in patients 3 months to 12 years of age is 15 mg/kg twice daily (not to exceed 1 g/day). Table 1 presents treatment guidelines for Ertapenem for Injection. Table 1: Treatment Guidelines for Adults and Pediatric Patients With Normal Renal Function defined as creatinine clearance >90 mL/min/1.73 m 2 and Body Weight Infection due to the designated pathogens [see Indications and Usage (1) ] Daily Dose (I.V. or I.M.) Adults and Pediatric Patients 13 years of age and older Daily Dose (I.V. or I.M.) Pediatric Patients 3 months to 12 years of age Recommended Duration of Total Antimicrobial Treatment Complicated intra-abdominal infections 1 g 15 mg/kg twice daily not to exceed 1 g/day 5 to 14 days Complicated skin and skin structure infections, including diabetic foot infections Ertapenem for Injection has not been studied in diabetic foot infections with concomitant osteomyelitis [see Clinical Studies (14.1) ] . 1 g 15 mg/kg twice daily 7 to 14 days adult patients with diabetic foot infections received up to 28 days of treatment (parenteral or parenteral plus oral switch therapy) Community acquired pneumonia 1 g 15 mg/kg twice daily 10 to 14 days duration includes a possible switch to an appropriate oral therapy, after at least 3 days of parenteral therapy, once clinical improvement has been demonstrated. Complicated urinary tract infections, including pyelonephritis 1 g 15 mg/kg twice daily 10 to 14 days Acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections 1 g 15 mg/kg twice daily 3 to 10 days 2.3 Prophylactic Regimen in Adults Table 2 presents prophylaxis guidelines for Ertapenem for Injection. Table 2: Prophylaxis Guidelines for Adults Indication Daily Dose (I.V.) Adults Recommended Duration of Total Antimicrobial Treatment Prophylaxis of surgical site infection following elective colorectal surgery 1 g Single intravenous dose given 1 hour prior to surgical incision 2.4 Patients with Renal Impairment Ertapenem for Injection may be used for the treatment of infections in adult patients with renal impairment. In patients whose creatinine cl …

3 DOSAGE FORMS AND STRENGTHS For Injection: Vials Ertapenem for injection is a sterile lyophilized powder in a single-dose vial containing 1 g ertapenem equivalent to 1.046 g ertapenem sodium for intravenous infusion or for intramuscular injection after reconstitution. For injection: Single-dose vial 1 gram. (3)

4 CONTRAINDICATIONS • Ertapenem for Injection is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams. • Due to the use of lidocaine HCl as a diluent, Ertapenem for Injection administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type. • Known hypersensitivity to product components or anaphylactic reactions to β-lactams. ( 4 ) • Due to the use of lidocaine HCl as a diluent, Ertapenem for Injection administered intramuscularly is contraindicated in patients with a known hypersensitivity to local anesthetics of the amide type. ( 4 )

6 ADVERSE REACTIONS The following are described in greater detail in the Warnings and Precautions section. • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] • Seizure Potential [see Warnings and Precautions (5.2) ] • Interaction with Valproic Acid [see Warnings and Precautions (5.3) ] • Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4) ] • Caution with Intramuscular Administration [see Warnings and Precautions (5.5) ] • Development of Drug-Resistant Bacteria [see Warnings and Precautions (5.6) ] • Laboratory Tests [see Warnings and Precautions (5.7) ] Adults: The most common adverse reactions (≥5%) in patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea, nausea, headache and infused vein complication. ( 6.1 ) In the prophylaxis indication the overall adverse experience profile was generally comparable to that observed for ertapenem in other clinical trials. ( 6.1 ) Pediatrics: Adverse reactions in this population were comparable to adults. The most common adverse reactions (≥5%) in pediatric patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea, vomiting and infusion site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults Receiving Ertapenem for Injection as a Treatment Regimen Clinical trials enrolled 1954 patients treated with Ertapenem for Injection; in some of the clinical trials, parenteral therapy was followed by a switch to an appropriate oral antimicrobial [see Clinical Studies (14) ] . Most adverse experiences reported in these clinical trials were described as mild to moderate in severity. Ertapenem for Injection was discontinued due to adverse experiences in 4.7% of patients. Table 3 shows the incidence of adverse experiences reported in ≥2% of patients in these trials. The most common drug-related adverse experiences in patients treated with Ertapenem for Injection, including those who were switched to therapy with an oral antimicrobial, were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), and vaginitis in females (2.1%). Table 3: Incidence (%) of Adverse Experiences Reported During Study Therapy Plus 14-Day Follow-Up in ≥2% of Adult Patients Treated With Ertapenem for Injection in Clinical Trials Ertapenem for Injection Includes Phase IIb/III Complicated intra-abdominal infections, Complicated skin and skin structure infections and Acute pelvic infections trials 1 g daily Piperacillin/ Tazobactam 3.375 g q6h Ertapenem for Injection Includes Phase IIb/III Community acquired pneumonia and Complicated urinary tract infections, and Phase IIa trials 1 g daily Ceftriaxone 1 or 2 g daily Adverse Events (N=802) (N=774) (N=1152) (N=942) Local: Infused vein complication 7.1 7.9 5.4 6.7 Systemic: Death 2.5 1.6 1.3 1.6 Edema/swelling 3.4 2.5 2.9 3.3 Fever 5 6.6 2.3 3.4 Abdominal pain 3.6 4.8 4.3 3.9 Hypotension 2 1.4 1 1.2 Constipation 4 5.4 3.3 3.1 Diarrhea 10.3 12.1 9.2 9.8 Nausea 8.5 8.7 6.4 7.4 Vomiting 3.7 5.3 4 4 Altered mental status Includes agitation, confusion, disorientation, decreased mental acuity, changed mental status, somnolence, stupor 5.1 3.4 3.3 2.5 Dizziness 2.1 3 1.5 2.1 Headache 5.6 5.4 6.8 6.9 Insomnia 3.2 5.2 3 4.1 Dyspnea 2.6 1.8 1 2.4 Pruritus 2 2.6 1 1.9 Rash 2.5 3.1 2.3 1.5 Vaginitis 1.4 1 3.3 3.7 In patients treated for complicated intra-abdominal infections, death occurred in 4.7% (15/316) of patients receiving Ertapenem for Injection and 2.6% (8 …

7 DRUG INTERACTIONS • Co-administration with probenecid inhibits the renal excretion of ertapenem and is therefore not recommended. ( 7.1 ) • The concomitant use of ertapenem and valproic acid/divalproex sodium is generally not recommended. Anti-bacterials other than carbapenems should be considered to treat infections in patients whose seizures are well controlled on valproic acid or divalproex sodium. ( 5.2 , 7.2 ) 7.1 Probenecid Probenecid interferes with the active tubular secretion of ertapenem, resulting in increased plasma concentrations of ertapenem [see Clinical Pharmacology (12.3) ] . Co-administration of probenecid with ertapenem is not recommended. 7.2 Valproic Acid Case reports in the literature have shown that co-administration of carbapenems, including ertapenem, to patients receiving valproic acid or divalproex sodium results in a reduction of valproic acid concentrations. The valproic acid concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies suggest that carbapenems may inhibit the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid, thus decreasing the serum concentrations of valproic acid [see Warnings and Precautions (5.3) ] .

8 USE IN SPECIFIC POPULATIONS • Renal Impairment: Dose adjustment is necessary, if creatinine clearance is ≤30 mL/min/1.73 m 2 . ( 2.4 , 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary Available data from a small number of postmarketing cases with Ertapenem for Injection use in pregnancy are insufficient to inform any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies after intravenous administration of ertapenem during the period of organogenesis, there was no evidence of developmental malformations in rats at systemic exposures (AUC) up to approximately 1.2 times the human exposure at the maximum recommended human dose (MRHD) and in mice at doses up to approximately 3 times the MRHD based on body surface area comparison. In pregnant rats administered ertapenem during organogenesis through lactation, fetal toxicity, developmental delays, and impaired reproduction did not occur in first generation offspring at systemic exposures (AUC) approximately 1.2 times the human exposure at the MRHD (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In pregnant rats, intravenous administration of ertapenem dosages of up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during the period of organogenesis (gestation days [GD] 6-20) revealed no maternal or embryofetal effects. Pregnant mice intravenously administered ertapenem dosages of up to 700 mg/kg/day (approximately 3 times the MRHD based on body surface area comparison) during the period of organogenesis (GD 6-15) showed slight decreases in average fetal weight and an associated decrease in the average number of ossified sacrocaudal vertebrae. There were no maternal effects at any dosage. In a pre-postnatal study in rats, ertapenem administered to pregnant rats at dosages up to 700 mg/kg/day (approximately 1.2 times the MRHD based on AUC) during organogenesis through lactation, (GD 6 until Lactation Day (LD) 20) did not result in fetal toxicity, developmental delays, or impaired reproduction in first generation offspring, and fetal deaths and malformations were not increased in second generation offspring. 8.2 Lactation Risk Summary Ertapenem is present in human milk (see Data) . There are no data on the effects on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Ertapenem for Injection and any potential adverse effects on the breastfed infant from Ertapenem for Injection or from the underlying maternal condition. Data The concentration of ertapenem in breast milk from 5 lactating women with pelvic infections (5 to 14 days postpartum) measured at random time points daily for 5 consecutive days following the last 1 g dose of intravenous therapy (3 to 10 days of therapy) showed low levels. The concentration of ertapenem in breast milk within 24 hours of the last dose of therapy in all 5 women ranged from (<0.13 (lower limit of quantitation) to 0.38 mcg/ml), although peak concentrations were not assessed. By day 5 after discontinuation of therapy, the level of ertapenem was undetectable in the breast milk of 4 women and below the lower limit of quantitation (<0.13 mcg/mL) in 1 woman. The concentration of ertapenem in transitional milk observed in this study may not reflect the concentration of ertapenem in mature milk. 8.4 Pediatric Use Safety and effectiveness of Ertapenem for Injection in pediatric patients 3 months to 17 years of age are supported by evidence from adequate and well-controlled trials in adults, pharmacokinetic d …

12.1 Mechanism of Action Ertapenem sodium is a carbapenem antibiotic [see Clinical Pharmacology ( 12.4 )].

11 DESCRIPTION Ertapenem for Injection is a sterile, synthetic, parenteral, 1-β methyl-carbapenem that is structurally related to beta-lactam antibiotics. Chemically, Ertapenem for Injection is described as [4 R -[3(3 S *,5 S *),4α,5β,6β( R *)]]-3-[[5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt. Its molecular weight is 497.5. The empirical formula is C 22 H 24 N 3 O 7 SNa, and its structural formula is: Ertapenem sodium is a white to off-white hygroscopic, weakly crystalline powder. It is soluble in water and 0.9% sodium chloride solution, practically insoluble in ethanol, and insoluble in isopropyl acetate and tetrahydrofuran. Ertapenem for Injection is supplied as sterile lyophilized powder for intravenous infusion after reconstitution with appropriate diluent [see Dosage and Administration (2.7) ] and transfer to 50 mL 0.9% Sodium Chloride Injection or for intramuscular injection following reconstitution with 1% lidocaine hydrochloride. Each single-dose vial contains 1 gram ertapenem sodium equivalent to 1.046 grams ertapenem sodium. The sodium content is approximately 137 mg (approximately 6 mEq). Each vial of Ertapenem for Injection contains the following inactive ingredients: 175 mg sodium bicarbonate and sodium hydroxide to adjust pH to 7.5. structural formula

10 OVERDOSAGE No specific information is available on the treatment of overdosage with Ertapenem for Injection. Intentional overdosing of Ertapenem for Injection is unlikely. Intravenous administration of Ertapenem for Injection at a dose of 2 g over 30 min or 3 g over 1 to 2h in healthy adult volunteers resulted in an increased incidence of nausea. In clinical trials in adults, inadvertent administration of three 1 g doses of Ertapenem for Injection in a 24 hour period resulted in diarrhea and transient dizziness in one patient. In pediatric clinical trials, a single intravenous dose of 40 mg/kg up to a maximum of 2 g did not result in toxicity. In the event of an overdose, Ertapenem for Injection should be discontinued and general supportive treatment given until renal elimination takes place. Ertapenem for Injection can be removed by hemodialysis; the plasma clearance of the total fraction of ertapenem was increased 30% in subjects with end-stage renal disease when hemodialysis (4 hour session) was performed immediately following administration. However, no information is available on the use of hemodialysis to treat overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Ertapenem for injection is supplied as a sterile lyophilized powder in single dose vials containing ertapenem for intravenous infusion or for intramuscular injection as follows: NDC Ertapenem For Injection Package Factor 43598-901-58 1g Single Dose Vial 10 vials per carton 16.2 Storage and Handling Before reconstitutionDo not store lyophilized powder above 25°C (77°F). Reconstituted and infusion solutions The reconstituted solution, immediately diluted in 0.9% Sodium Chloride Injection [see Dosage and Administration (2.7)], may be stored at room temperature at room temperature (25°C) and used within 6 hours or stored for 24 hours under refrigeration (5°C) and used within 4 hours after removal from refrigeration. Solutions of Ertapenem for injection should not be frozen.